Cardiac output and organ blood flow are increased during both tissue hypoxia and hypermetabolism. The long-range plan of our research is to investigate the regulatory mechanisms of these circulatory changes in response to tissue oxygen demand. We have studied the cardiac output responses to arterial hypoxemia, cyanide infusion, muscular exercise and 2,4-dinitrophenol infusion. We plan to further study the distribution of cardiac output to various organs in the body using the microsphere technique during these experimental conditions. We will also employ techniques of cross-circulation, pharmacological blockade and extirpation of organs to investigate the transmission pathways and final cardiostimulatory mechanisms which are responsible for the circulatory stimulation during hypermetabolic and hypoxic states. Thereafter, several specific metabolic inhibitors and substrates will be administered to animals in an attempt to identify the specific metabolic factors that cause the circulatory stimulation. Cardiac failure is characterized by a diminished response of cardiac output to tissue oxygen demand; a failure of cardiac output to increase may be caused by a defect in any part of the mechanisms through which such "information" regarding tissue oxygen demand is transmitted to the heart. The elucidation of the complex metabolic regulation of cardiac output will clarify the pathophysiology of certain kinds of heart failure and provide us with a guide for its treatment.